Legislation
Resolution

Resolution - RE nº 479, of March 19, 2002
(Official Journal of 20/03/2002)

>> See also GUIDE FOR DESIGNS APPLICABLE TO BIOEQUIVALENCE STUDIES

The Director of the Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in him under Administrative Rule 724, issued by the Director-Chairman, on October 10, 2000,

WHEREAS

paragraph 3 of article 111, of the Bylaws approved by Administrative Rule 593, of August 25, 2000, re-published in the Official Journal of the Union of December 22, 2000;
that the matter was submitted to the examination of the Collegiate Board of Directors, which approved the matter in a meeting held on March 13, 2002, decides:

Article 1 - To determine the publication of the "Guide for Protocol and Technical Report of Bioequivalence Study", attached.

Article 2 - This Resolution enters into force on the date of its publication.

GONZALO VECINA NETO

GUIDE FOR PROTOCOL AND TECHNICAL REPORT OF BIOEQUIVALENCE STUDY - 1/2002

1. title of the project (must contain the name of the drug, strength, dosage form and name of manufacturer of the test and the reference drug products);

2. main investigator (researcher in charge);

3. clinical investigator (must necessarily be a physician);

4. protocol number and date;

5. study objective;

6. study design:

6.1. type;
6.2. test and reference drug products (description, batch number, date of manufacture, expiry date, etc);
6.3. dosage (dose and volume of liquid for administration);
6.4. housing of subjects;
6.5. fasting and feeding time table;
6.6. sampling schedule;
6.7. sample manipulation procedures;
6.8. analytical methods;

7. population of the study:

7.1. detailed description (sex, age, weight, height);
7.2. subject selection:
7.2.1. clinical assessment (medical history and physical exam);
7.2.2. clinical laboratory exams: electrocardiogram, hematological and biochemical exams (including proofs of hepatic and renal function), serological exams (Hepatitis B, Hepatitis C, HIV), beta HCG (for women) and urine type I.
7.3. inclusion criteria;
7.4. exclusion criteria;
7.5. restrictions and prohibitions: before, during and after study;
7.6. criteria for subject discontinuation or withdrawal from the study;

8. adverse reactions and emergency procedures;

9. ethical considerations:
9.1. basic principles - must follow the resolutions in force of the National Health Council-Ministry of Health (CNS/MS), which regulate the research norms on human beings;
9.2. report from the Committee of Ethics in Research accredited by the National Committee of Ethics in Research (CONEP) of the National Health Council-Ministry of Health (CNS/MS);

10. data analysis:
10.1. validation of the analytical methods;
10.2. statistical treatment;
10.2.1. present study design, according to Annex XI.
10.2.2. specify size of the sample in the study.
10.2.3. the acceptance interval of the pharmacokinetics parameters to be tested in the study must be previously defined.
10.2.4. specify outlier detection method.

11. appendixes;
11.1 retention samples (the number of units of the test and the reference drug products that are to be retained (enough to repeat the study) must be informed. These samples must be stored in proper conditions to preserve the original characteristics of the products up to their expiry date;
11.2. inventory of the drug products used in the study (the number of units of test and reference drug products used in the study, as well as any occurring loss, must be informed);
11.3. model of informed consent form;
11.4. adverse events charts;
11.5. randomization list

12. the documents to be submitted to ANVISA, together with the technical report of the bioequivalence study, are:
12.1. validation study data;
12.1.1. validation report in chronological sequence, with description of the analytical method employed, including identification of codes and causes of additional validations, when necessary;
12.1.2. certificates or analytical reports on the standards of the drug product and/or metabolite used;
12.1.3. description of the stability studies and results achieved;
12.1.4. description of the assays carried out for determining accuracy and precision (intra and inter runs), recovery, selectivity, quantification limit, calibration curve (with respective equations) and results achieved;
12.2. chart listing calibration curves with their respective dates, correlation coefficient equations, values obtained from standards with nominal deviations and identifications of samples calculated for each curve;
12.3. analytical runs validation (values obtained from quality controls and their respective nominal deviations);
12.4. complete series of the chromatograms of 20% of the subjects, with calibration curves and quality controls;
12.4.1. data from the chromatograms: identification of the study, of analyst, of sample (for example, subject, period and collection time), date and time of the injection, retention time values and peak areas of the analyte and internal standard;
12.5. report on reanalysis of the samples, including initial and repeated results, identification of the runs and the causes, in compliance with standard operational procedures (SOP);
12.6. all the standard operational procedures (SOP) of the analytical part, original data, concentration calculations, re-analysis of samples including:
12.6.1. criteria for acceptance or rejection of the concentration values of the calibration curve;
12.6.2. criteria for acceptance or rejection of the calibration curve;
12.6.3. criteria for acceptance or rejection of the quality control samples and of the analytical run;
12.6.4. acceptance criteria for reported values when all the samples are analyzed in duplicate or triplicate;
12.6.5. sample collection, processing and storage;
12.7. procedure for transporting biological liquid samples, whenever the case;
12.8. clinical procedures- SOP of the clinical part: instructions to the subject, samples identification, blood collection procedure, drug products administration procedure;
12.9. chart containing date and time of collection of the samples from all the subjects;
12.10. chart containing all the pharmacokinetic parameters listed in item 6.3.2 (general methodology) calculated for all the subjects at each stage of the study;
12.11. protocol deviations report.
Obs: 1 All the documentation submitted, concerning the clinical and analytical phases, must be signed by the respective people in charge.
Obs: 2 The technical report about the bioequivalence study must be returned in two printed copies and one copy in diskette with a spreadsheet in MS-Excel with the results of the pharmacokinetics parameters calculated separately (ASC0-t, Cmax e Tmax), and the individual values of the plasmatic drug concentrations, for all the phases of the study.
Obs: 3 The study protocol, in two copies, must be handed in together with the technical report.